DNA methylation patterns as noninvasive biomarkers and targets of epigenetic therapies in colorectal cancer

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

• 1 Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J. Clin. 60(5), 277–300 (2010).
  MedlineGoogle Scholar
• 2 Taylor DP, Cannon-Albright LA, Sweeney C et al. Comparison of compliance for colorectal cancer screening and surveillance by colonoscopy based on risk. Genet. Med. 13(8), 737–743 (2011).
  MedlineGoogle Scholar
• 3 Cappell MS, Friedel D. The role of sigmoidoscopy and colonoscopy in the diagnosis and management of lower gastrointestinal disorders: endoscopic findings, therapy, and complications. Med. Clin. North Am. 86(6), 1253–1288 (2002).
  MedlineGoogle Scholar
• 4 Warren JL, Klabunde CN, Mariotto AB et al. Adverse events after outpatient colonoscopy in the Medicare population. Ann. Intern. Med. 150(12), 849–857; W152 (2009).
  MedlineGoogle Scholar
• 5 Polter DE. Risk of colon perforation during colonoscopy at Baylor University Medical Center. Proc. (Bayl. Univ. Med. Cent.) 28(1), 3–6 (2015).
  MedlineGoogle Scholar
• 6 Gardiner-Garden M, Frommer M. CpG islands in vertebrate genomes. J. Mol. Biol. 196(2), 261–282 (1987).
  Medline CASGoogle Scholar
• 7 Baylin SB, Hoppener JW, De Bustros A, Steenbergh PH, Lips CJ, Nelkin BD. DNA methylation patterns of the calcitonin gene in human lung cancers and lymphomas. Cancer Res. 46(6), 2917–2922 (1986).
  Medline CASGoogle Scholar
• 8 Moutinho C, Martinez-Cardus A, Santos C et al. Epigenetic inactivation of the BRCA1 interactor SRBC and resistance to oxaliplatin in colorectal cancer. J. Natl Cancer Inst. 106(1), djt322 (2014). • The authors discovered that methylation-associated inactivation of the SRBC gene, which interacts with BRCA1, contributes to oxaliplatin resistance in colorectal cancer cells, and SRBC hypermethylation was associated with shorter progression-free survival in patients with unresectable colorectal tumors treated with oxaliplatin.
  MedlineGoogle Scholar
• 9 Hilger-Eversheim K, Moser M, Schorle H, Buettner R. Regulatory roles of AP-2 transcription factors in vertebrate development, apoptosis and cell-cycle control. Gene 260(1–2), 1–12 (2000).
  Medline CASGoogle Scholar
• 10 Iavarone A, Massague J. Repression of the CDK activator Cdc25A and cell-cycle arrest by cytokine TGF-beta in cells lacking the CDK inhibitor p15. Nature 387(6631), 417–422 (1997).
  Medline CASGoogle Scholar
• 11 Benard A, Zeestraten EC, Goossens-Beumer IJ et al. DNA methylation of apoptosis genes in rectal cancer predicts patient survival and tumor recurrence. Apoptosis 19(11), 1581–1593 (2014).
  Medline CASGoogle Scholar
• 12 Rajah R, Valentinis B, Cohen P. Insulin-like growth factor (IGF)-binding protein-3 induces apoptosis and mediates the effects of transforming growth factor-beta1 on programmed cell death through a p53- and IGF-independent mechanism. J. Biol. Chem. 272(18), 12181–12188 (1997).
  Medline CASGoogle Scholar
• 13 Baba Y, Nosho K, Shima K et al. Hypomethylation of the IGF2 DMR in colorectal tumors, detected by bisulfite pyrosequencing, is associated with poor prognosis. Gastroenterology 139(6), 1855–1864 (2010). •• The authors were among the first to employ a bisulfite-pyrosequencing assay to a large cohort of paraffin-embedded colorectal cancer tissues to correlate hypomethylation of a specific tumor suppressor with shorter survival time, and suggest it as a prognostic biomarker.
  Medline CASGoogle Scholar
• 14 Ogino S, Nosho K, Kirkner GJ et al. A cohort study of tumoral LINE-1 hypomethylation and prognosis in colon cancer. J. Natl Cancer Inst. 100(23), 1734–1738 (2008).
  Medline CASGoogle Scholar
• 15 Rodriguez J, Frigola J, Vendrell E et al. Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers. Cancer Res. 66(17), 8462–9468 (2006).
  Medline CASGoogle Scholar
• 16 Yan PS, Perry MR, Laux DE, Asare AL, Caldwell CW, Huang TH. CpG island arrays: an application toward deciphering epigenetic signatures of breast cancer. Clin. Cancer. Res. 6(4), 1432–1438 (2000).
  Medline CASGoogle Scholar
• 17 Esteller M. The necessity of a human epigenome project. Carcinogenesis 27(6), 1121–1125 (2006).
  Medline CASGoogle Scholar
• 18 Meissner A, Gnirke A, Bell GW, Ramsahoye B, Lander ES, Jaenisch R. Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis. Nucleic Acids. Res. 33(18), 5868–5877 (2005).
  Medline CASGoogle Scholar
• 19 Shima K, Morikawa T, Baba Y et al. MGMT promoter methylation, loss of expression and prognosis in 855 colorectal cancers. Cancer Causes Control 22(2), 301–309 (2011).
  MedlineGoogle Scholar
• 20 Krtolica K, Krajnovic M, Usaj-Knezevic S, Babic D, Jovanovic D, Dimitrijevic B. Comethylation of p16 and MGMT genes in colorectal carcinoma: correlation with clinicopathological features and prognostic value. World J. Gastroenterol. 13(8), 1187–1194 (2007).
  Medline CASGoogle Scholar
• 21 Nilsson TK, Lof-Ohlin ZM, Sun XF. DNA methylation of the p14ARF, RASSF1A and APC1A genes as an independent prognostic factor in colorectal cancer patients. Int. J. Oncol. 42(1), 127–133 (2013).
  Medline CASGoogle Scholar
• 22 Murai M. Aberrant methylation and silencing of the BNIP3 gene in colorectal and gastric cancer. Clin. Cancer Res. 11(3), 1–8 (2005).
  Google Scholar
• 23 Mittag F, Kuester D, Vieth M et al. DAPK promotor methylation is an early event in colorectal carcinogenesis. Cancer Lett. 240(1), 69–75 (2006).
  Medline CASGoogle Scholar
• 24 Heitzer E, Artl M, Filipits M et al. Differential survival trends of stage II colorectal cancer patients relate to promoter methylation status of PCDH10, SPARC, and UCHL1. Mod. Pathol. 27(6), 906–915 (2013).
  MedlineGoogle Scholar
• 25 Chen WD, Han ZJ, Skoletsky J et al. Detection in fecal DNA of colon cancer-specific methylation of the nonexpressed vimentin gene. J. Natl Cancer Inst. 97(15), 1124–1132 (2005).
  Medline CASGoogle Scholar
• 26 Draht MX, Smits KM, Tournier B et al. Promoter CpG island methylation of RET predicts poor prognosis in stage II colorectal cancer patients. Mol. Oncol. 8(3), 679–688 (2014).
  Medline CASGoogle Scholar
• 27 Bachman KE, Herman JG, Corn PG, Merlo A, Cavenee WK, Baylin SB. Methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene suggests a suppressor role in kidney, brain, and other human cancers. Cancer Res. 59(4), 1–6 (1999).
  Google Scholar
• 28 Barault L, Charon-Barra C, Jooste V et al. Hypermethylator phenotype in sporadic colon cancer: study on a population-based series of 582 cases. Cancer Res. 68(20), 8541–8546 (2008).
  Medline CASGoogle Scholar
• 29 Ishiguro A, Takahata T, Saito M et al. Influence of methylated p15 and p16 genes on clinicopathological features in colorectal cancer. J. Gastroenterol. Hepatol. 21(8), 1334–1339 (2006).
  Medline CASGoogle Scholar
• 30 Watanabe Y, Toyota M, Kondo Y et al. PRDM5 identified as a target of epigenetic silencing in colorectal and gastric cancer. Clin. Cancer Res. 13(16), 4786–4794 (2007).
  Medline CASGoogle Scholar
• 31 Hiranuma C, Kawakami K, Oyama K, Ota N, Omura K, Watanabe G. Hypermethylation of the MYOD1 gene is a novel prognostic factor in patients with colorectal cancer. Int. J. Mol. Med. 13(3), 413–417 (2004).
  Medline CASGoogle Scholar
• 32 Miladi-Abdennadher I, Abdelmaksoud-Damak R, Ayadi L et al. Hypermethylation of RARbeta2 correlates with high COX-2 expression and poor prognosis in patients with colorectal carcinoma. Tumour Biol. 31(5), 503–511 (2010).
  Medline CASGoogle Scholar
• 33 Hellebrekers DMEI, Lentjes MHFM, Van Den Bosch SM et al. GATA4 and GATA5 are potential tumor suppressors and biomarkers in colorectal cancer. Clin. Cancer Res. 15(12), 3990–3997 (2009).
  Medline CASGoogle Scholar
• 34 Dallol A, Al-Maghrabi J, Buhmeida A et al. Methylation of the polycomb group target genes is a possible biomarker for favorable prognosis in colorectal cancer. Cancer Epidemiol. Biomarkers Prev. 21(11), 2069–2075 (2012).
  Medline CASGoogle Scholar
• 35 Zhang ZM, Wang Y, Huang R et al. TFAP2E hypermethylation was associated with survival advantage in patients with colorectal cancer. J. Cancer Res. Clin. Oncol. 140(12), 2119–2127 (2014).
  Medline CASGoogle Scholar
• 36 Wallner M, Herbst A, Behrens A et al. Methylation of serum DNA is an independent prognostic marker in colorectal cancer. Clin. Cancer Res. 12(24), 7347–7352 (2006).
  Medline CASGoogle Scholar
• 37 Rawson JB, Manno M, Mrkonjic M et al. Promoter methylation of Wnt antagonists DKK1 and SFRP1 is associated with opposing tumor subtypes in two large populations of colorectal cancer patients. Carcinogenesis 32(5), 741–747 (2011).
  Medline CASGoogle Scholar
• 38 Takeda M. Expansion of CpG methylation in the SFRP2 promoter region during colorectal tumorigenesis. Acta Med. Okayama 65(3), 169–177 (2011).
  Medline CASGoogle Scholar
• 39 Tang D, Liu J, Wang DR, Yu HF, Li YK, Zhang JQ. Diagnostic and prognostic value of the methylation status of secreted frizzled-related protein 2 in colorectal cancer. Clin. Invest. Med. 34(2), E88–E95 (2011).
  MedlineGoogle Scholar
• 40 Silva A-L, Dawson SN, Arends MJ et al. Boosting Wnt activity during colorectal cancer progression through selective hypermethylation of Wnt signaling antagonists. BMC Cancer 14(1), 891–810 (2014).
  MedlineGoogle Scholar
• 41 Sato H, Suzuki H, Toyota M et al. Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors. Carcinogenesis 28(12), 2459–2466 (2007).
  Medline CASGoogle Scholar
• 42 Abdelmaksoud-Dammak R, Miladi-Abdennadher I, Saadallah-Kallel A et al. Downregulation of WIF-1 and Wnt5a in patients with colorectal carcinoma: clinical significance. Tumour Biol. 35(8), 7975–7982 (2014).
  Medline CASGoogle Scholar
• 43 Hesson LB, Wilson R, Morton D et al. CpG island promoter hypermethylation of a novel Ras-effector gene RASSF2A is an early event in colon carcinogenesis and correlates inversely with K-ras mutations. Oncogene 24(24), 3987–3994 (2005).
  Medline CASGoogle Scholar
• 44 Hibi K, Goto T, Kitamura Y-H et al. Methylation of TFPI2 gene is frequently detected in advanced well-differentiated colorectal cancer. Anticancer Res. 30(4), 1205–1207 (2010).
  Medline CASGoogle Scholar
• 45 Gerecke C, Scholtka B, Löwenstein Y et al. Hypermethylation of ITGA4, TFPI2 and VIMENTIN promoters is increased in inflamed colon tissue: putative risk markers for colitis-associated cancer. J. Cancer Res. Clin. Oncol. 141(12), 1–11 (2015).
  MedlineGoogle Scholar
• 46 Perez-Carbonell L, Balaguer F, Toiyama Y et al. IGFBP3 methylation is a novel diagnostic and predictive biomarker in colorectal cancer. PLoS ONE 9(8), e104285 (2014).
  MedlineGoogle Scholar
• 47 Melotte V, Lentjes MHFM, Van Den Bosch SM et al. N-Myc downstream-regulated gene 4 (NDRG4): a candidate tumor suppressor gene and potential biomarker for colorectal cancer. J. Natl Cancer Inst. 101(13), 916–927 (2009).
  Medline CASGoogle Scholar
• 48 De Maat MF, Van De Velde CJ, Van Der Werff MP et al. Quantitative analysis of methylation of genomic loci in early-stage rectal cancer predicts distant recurrence. J. Clin. Oncol. 26(14), 2327–2335 (2008).
  Medline CASGoogle Scholar
• 49 Chen SP, Chiu SC, Wu CC et al. The association of methylation in the promoter of APC and MGMT and the prognosis of Taiwanese CRC patients. Genet. Test. Mol. Biomarkers 13(1), 67–71 (2009).
  Medline CASGoogle Scholar
• 50 Gaudet F, Talbot D, Leonhardt H, Jaenisch R. A short DNA methyltransferase isoform restores methylation in vivo. J. Biol. Chem. 273(49), 32725–32729 (1998).
  Medline CASGoogle Scholar
• 51 Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99(3), 247–257 (1999).
  Medline CASGoogle Scholar
• 52 Li W, Zheng J, Deng J et al. Increased levels of the long intergenic non-protein coding RNA POU3F3 promote DNA methylation in esophageal squamous cell carcinoma cells. Gastroenterology 146(7), 1714–1726; e1715 (2014).
  Medline CASGoogle Scholar
• 53 Di Ruscio A, Ebralidze AK, Benoukraf T et al. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature 503(7476), 371–376 (2013).
  Medline CASGoogle Scholar
• 54 Wu D, Fu H, Zhou H, Su J, Zhang F, Shen J. Effects of novel ncRNA mmolecules, p15-piRNAs, on the methylation of DNA and histone H3 of the CDKN2B promoter region in U937 cells. J. Cell Biochem. 116(12), 2744–2754 (2015). •• The authors were the first to discover that noncoding RNA binds to DNMT1 to prevent CEBPA locus methylation. These data suggest a novel epigenetic mechanism that control methylation patterns.
  Medline CASGoogle Scholar
• 55 Aravin AA, Sachidanandam R, Bourc'his D et al. A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice. Mol. Cell 31(6), 785–799 (2008).
  Medline CASGoogle Scholar
• 56 Meehan R, Antequera F, Lewis J et al. A nuclear protein that binds preferentially to methylated DNA in vitro may play a role in the inaccessibility of methylated CpGs in mammalian nuclei. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 326(1235), 199–205 (1990).
  Medline CASGoogle Scholar
• 57 Bell AC, Felsenfeld G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405(6785), 482–485 (2000).
  Medline CASGoogle Scholar
• 58 Wilson VL, Smith RA, Ma S, Cutler RG. Genomic 5-methyldeoxycytidine decreases with age. J. Biol. Chem. 262(21), 9948–9951 (1987).
  Medline CASGoogle Scholar
• 59 Graff JR, Herman JG, Myöhänen S, Baylin SB, Vertino PM. Mapping patterns of CpG island methylation in normal and neoplastic cells implicates both upstream and downstream regions in de novo methylation. J. Biol. Chem. 272(35), 22322–22329 (1997).
  Medline CASGoogle Scholar
• 60 Finkelstein JD. Methionine metabolism in mammals. J. Nutr. Biochem. 1(5), 228–237 (1990).
  Medline CASGoogle Scholar
• 61 Lashner BA, Heidenreich PA, Su GL, Kane SV, Hanauer SB. Effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis. A case–control study. Gastroenterology 97(2), 255–259 (1989).
  Medline CASGoogle Scholar
• 62 Hu Y, Su L, Snow ET. Arsenic toxicity is enzyme specific and its affects on ligation are not caused by the direct inhibition of DNA repair enzymes. Mutat. Res. 408(3), 203–218 (1998).
  Medline CASGoogle Scholar
• 63 Mass MJ, Wang L. Arsenic alters cytosine methylation patterns of the promoter of the tumor suppressor gene p53 in human lung cells: a model for a mechanism of carcinogenesis. Mutat. Res. 386(3), 263–277 (1997).
  Medline CASGoogle Scholar
• 64 Glynn SA, Albanes D, Pietinen P et al. Colorectal cancer and folate status: a nested case–control study among male smokers. Cancer Epidemiol. Biomarkers Prev. 5(7), 487–494 (1996).
  Medline CASGoogle Scholar
• 65 Issa JP, Ahuja N, Toyota M, Bronner MP, Brentnall TA. Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res. 61(9), 3573–3577 (2001).
  Medline CASGoogle Scholar
• 66 Abu-Remaileh M, Bender S, Raddatz G et al. Chronic inflammation induces a novel epigenetic program that is conserved in intestinal adenomas and in colorectal cancer. Cancer Res. 75(10), 2120–2130 (2015).
  Medline CASGoogle Scholar
• 67 MacEachern SJ, Patel BA, Keenan CM et al. Inhibiting inducible nitric oxide synthase in enteric glia restores electrogenic ion transport in mice with colitis. Gastroenterology 149(2), 445.e443–455.e443 (2015).
  Google Scholar
• 68 Tominaga K. Prediction of colorectal neoplasia by quantitative methylation analysis of estrogen receptor gene in nonneoplastic epithelium from patients with ulcerative colitis. Clin. Cancer Res. 11(24), 8880–8885 (2005).
  Medline CASGoogle Scholar
• 69 Caldwell GM, Jones C, Gensberg K et al. The Wnt antagonist sFRP1 in colorectal tumorigenesis. Cancer Res. 64(3), 883–888 (2004).
  Medline CASGoogle Scholar
• 70 Deng QD, Huang S. PRDM5 is silenced in human cancers and has growth suppressive activities. Oncogene 23(28), 4903–4910 (2004).
  Medline CASGoogle Scholar
• 71 Grimm C, Sporle R, Schmid TE et al. Isolation and embryonic expression of the novel mouse gene Hic1, the homologue of HIC1, a candidate gene for the Miller–Dieker syndrome. Hum. Mol. Genet. 8(4), 697–710 (1999).
  Medline CASGoogle Scholar
• 72 Hsu CH, Peng KL, Kang ML et al. TET1 suppresses cancer invasion by activating the tissue inhibitors of metalloproteinases. Cell Rep. 2(3), 568–579 (2012).
  Medline CASGoogle Scholar
• 73 Esteller M, Risques RA, Toyota M et al. Promoter hypermethylation of the DNA repair gene O(6)-methylguanine-DNA methyltransferase is associated with the presence of G:C to A:T transition mutations in p53 in human colorectal tumorigenesis. Cancer Res. 61(12), 4689–4692 (2001).
  Medline CASGoogle Scholar
• 74 Nagasaka T, Goel A, Notohara K et al. Methylation pattern of the O6-methylguanine-DNA methyltransferase gene in colon during progressive colorectal tumorigenesis. Int. J. Cancer 122(11), 2429–2436 (2008).
  Medline CASGoogle Scholar
• 75 Cunningham JM, Christensen ER, Tester DJ et al. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res. 58(15), 3455–3460 (1998).
  Medline CASGoogle Scholar
• 76 Li X, Yao X, Wang Y et al. MLH1 promoter methylation frequency in colorectal cancer patients and related clinicopathological and molecular features. PLoS ONE 8(3), e59064 (2013).
  Medline CASGoogle Scholar
• 77 Shima K, Nosho K, Baba Y et al. Prognostic significance of CDKN2A (p16) promoter methylation and loss of expression in 902 colorectal cancers: cohort study and literature review. Int. J. Cancer 128(5), 1080–1094 (2011).
  Medline CASGoogle Scholar
• 78 Beggs AD, Domingo E, Abulafi M, Hodgson SV, Tomlinson IP. A study of genomic instability in early preneoplastic colonic lesions. Oncogene 32(46), 5333–5337 (2013).
  Medline CASGoogle Scholar
• 79 Oue N, Shigeishi H, Kuniyasu H et al. Promoter hypermethylation of MGMT is associated with protein loss in gastric carcinoma. Int. J. Cancer 93(6), 805–809 (2001).
  Medline CASGoogle Scholar
• 80 Esteller M, Toyota M, Sanchez-Cespedes M et al. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. Cancer Res. 60(9), 2368–2371 (2000).
  Medline CASGoogle Scholar
• 81 Chen WY, Wang DH, Yen RC, Luo J, Gu W, Baylin SB. Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 123(3), 437–448 (2005).
  Medline CASGoogle Scholar
• 82 Elmore S. Apoptosis: a review of programmed cell death. Toxicol. Pathol. 35(4), 495–516 (2007).
  Medline CASGoogle Scholar
• 83 Chung SK, Lee MG, Ryu BK et al. Frequent alteration of XAF1 in human colorectal cancers: implication for tumor cell resistance to apoptotic stresses. Gastroenterology 132(7), 2459–2477 (2007).
  Medline CASGoogle Scholar
• 84 Shimizu S, Iida S, Ishiguro M et al. Methylated BNIP3 gene in colorectal cancer prognosis. Oncol. Lett. 1(5), 865–872 (2010).
  Medline CASGoogle Scholar
• 85 Zhang J, Chen S, Zhang W et al. Human differentiation-related gene NDRG1 is a Myc downstream-regulated gene that is repressed by Myc on the core promoter region. Gene 417(1–2), 5–12 (2008).
  Medline CASGoogle Scholar
• 86 Feng L, Xie Y, Zhang H, Wu Y. Down-regulation of NDRG2 gene expression in human colorectal cancer involves promoter methylation and microRNA-650. Biochem. Biophys. Res. Commun. 406(4), 534–538 (2011).
  Medline CASGoogle Scholar
• 87 Xiao W, Zhao H, Dong W et al. Quantitative detection of methylated NDRG4 gene as a candidate biomarker for diagnosis of colorectal cancer. Oncol. Lett. 9(3), 1383–1387 (2015).
  MedlineGoogle Scholar
• 88 Fry DW, Harvey PJ, Keller PR et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol. Cancer Ther. 3(11), 1427–1438 (2004).
  Medline CASGoogle Scholar
• 89 Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88(5), 593–602 (1997).
  Medline CASGoogle Scholar
• 90 Goel A, Nagasaka T, Arnold CN et al. The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer. YGAST 132(1), 127–138 (2007).
  Medline CASGoogle Scholar
• 91 Mitomi H, Fukui N, Tanaka N et al. Aberrant p16(INK4a) methylation is a frequent event in colorectal cancers: prognostic value and relation to mRNA expression and immunoreactivity. J. Cancer Res. Clin. Oncol. 136(2), 323–331 (2010).
  Medline CASGoogle Scholar
• 92 Nakayama H, Hibi K, Taguchi M et al. Molecular detection of p16 promoter methylation in the serum of colorectal cancer patients. Cancer Lett. 188(1–2), 115–119 (2002).
  Medline CASGoogle Scholar
• 93 Nakayama H, Hibi K, Takase T et al. Molecular detection of p16 promoter methylation in the serum of recurrent colorectal cancer patients. Int. J. Cancer 105(4), 491–493 (2003).
  Medline CASGoogle Scholar
• 94 Herman JG, Merlo A, Mao L et al. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res. 55(20), 4525–4530 (1995).
  Medline CASGoogle Scholar
• 95 Kamekura R, Kolegraff KN, Nava P et al. Loss of the desmosomal cadherin desmoglein-2 suppresses colon cancer cell proliferation through EGFR signaling. Oncogene 33(36), 4531–4536 (2014).
  Medline CASGoogle Scholar
• 96 Lind GE, Thorstensen L, Lovig T et al. A CpG island hypermethylation profile of primary colorectal carcinomas and colon cancer cell lines. Mol. Cancer 3, 28 (2004).
  MedlineGoogle Scholar
• 97 Kroepil F, Fluegen G, Totikov Z et al. Down-regulation of CDH1 is associated with expression of SNAI1 in colorectal adenomas. PLoS ONE 7(9), e46665 (2012).
  Medline CASGoogle Scholar
• 98 Tange S, Oktyabri D, Terashima M, Ishimura A, Suzuki T. JARID2 is involved in transforming growth factor-beta-induced epithelial-mesenchymal transition of lung and colon cancer cell lines. PLoS ONE 9(12), e115684 (2014).
  MedlineGoogle Scholar
• 99 Nollet F, Kools P, Van Roy F. Phylogenetic analysis of the cadherin superfamily allows identification of six major subfamilies besides several solitary members. J. Mol. Biol. 299(3), 551–572 (2000).
  Medline CASGoogle Scholar
• 100 Zhong X, Zhu Y, Mao J, Zhang J, Zheng S. Frequent epigenetic silencing of PCDH10 by methylation in human colorectal cancer. J. Cancer Res. Clin. Oncol. 139(3), 485–490 (2013).
  Medline CASGoogle Scholar
• 101 Ying J, Li H, Seng TJ et al. Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation. Oncogene 25(7), 1070–1080 (2006).
  Medline CASGoogle Scholar
• 102 Britton C, McKerrow JH, Johnstone IL. Regulation of the Caenorhabditis elegans gut cysteine protease gene cpr-1: requirement for GATA motifs. J. Mol. Biol. 283(1), 15–27 (1998).
  Medline CASGoogle Scholar
• 103 Akiyama Y, Watkins N, Suzuki H et al. GATA-4 and GATA-5 transcription factor genes and potential downstream antitumor target genes are epigenetically silenced in colorectal and gastric cancer. Mol. Cell Biol. 23(23), 8429–8439 (2003).
  Medline CASGoogle Scholar
• 104 Eckert D, Buhl S, Weber S, Jäger R, Schorle H. The AP-2 family of transcription factors. Genome Biol. 6(13), 246 (2005).
  MedlineGoogle Scholar
• 105 Van Rechem C, Boulay G, Leprince D. HIC1 interacts with a specific subunit of SWI/SNF complexes, ARID1A/BAF250A. Biochem. Biophys. Res. Commun. 385(4), 586–590 (2009).
  Medline CASGoogle Scholar
• 106 Chen RH, McCormick F. Selective targeting to the hyperactive beta-catenin/T-cell factor pathway in colon cancer cells. Cancer Res. 61(11), 4445–4449 (2001).
  Medline CASGoogle Scholar
• 107 Chen J. Molecular analysis of APC promoter methylation and protein expression in colorectal cancer metastasis. Carcinogenesis 26(1), 37–43 (2004).
  Medline CASGoogle Scholar
• 108 Suzuki H, Gabrielson E, Chen W et al. A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat. Genet. 31(2), 141–149 (2002).
  Medline CASGoogle Scholar
• 109 Taniguchi H, Yamamoto H, Hirata T et al. Frequent epigenetic inactivation of Wnt inhibitory factor-1 in human gastrointestinal cancers. Oncogene 24(53), 7946–7952 (2005).
  Medline CASGoogle Scholar
• 110 Kawano Y, Kypta R. Secreted antagonists of the Wnt signalling pathway. J. Cell Sci. 116(Pt 13), 2627–2634 (2003).
  Medline CASGoogle Scholar
• 111 Fedi P, Bafico A, Nieto Soria A et al. Isolation and biochemical characterization of the human Dkk-1 homologue, a novel inhibitor of mammalian Wnt signaling. J. Biol. Chem. 274(27), 19465–19472 (1999).
  Medline CASGoogle Scholar
• 112 Van Engeland M, Roemen GM, Brink M et al. K-ras mutations and RASSF1A promoter methylation in colorectal cancer. Oncogene 21(23), 3792–3795 (2002).
  Medline CASGoogle Scholar
• 113 Buckbinder L, Talbott R, Velasco-Miguel S et al. Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature 377(6550), 646–649 (1995).
  Medline CASGoogle Scholar
• 114 Ebert MPA, Model F, Mooney S et al. Aristaless-like Homeobox-4 gene methylation is a potential marker for colorectal adenocarcinomas. Gastroenterology 131(5), 1418–1430 (2006).
  Medline CASGoogle Scholar
• 115 Grady WM, Rajput A, Lutterbaugh JD, Markowitz SD. Detection of aberrantly methylated hMLH1 promoter DNA in the serum of patients with microsatellite unstable colon cancer. Cancer Res. 61(3), 900–902 (2001).
  Medline CASGoogle Scholar
• 116 Leung WK, To KF, Man EP et al. Quantitative detection of promoter hypermethylation in multiple genes in the serum of patients with colorectal cancer. Am. J. Gastroenterol. 100(10), 2274–2279 (2005).
  Medline CASGoogle Scholar
• 117 Herbst A, Wallner M, Rahmig K et al. Methylation of helicase-like transcription factor in serum of patients with colorectal cancer is an independent predictor of disease recurrence. Eur. J. Gastroenterol. Hepatol. 21(5), 565–569 (2009).
  Medline CASGoogle Scholar
• 118 Philipp AB, Stieber P, Nagel D et al. Prognostic role of methylated free circulating DNA in colorectal cancer. Int. J. Cancer 131(10), 2308–2319 (2012).
  Medline CASGoogle Scholar
• 119 Philipp AB, Nagel D, Stieber P et al. Circulating cell-free methylated DNA and lactate dehydrogenase release in colorectal cancer. BMC Cancer 14, 245 (2014).
  MedlineGoogle Scholar
• 120 Herbst A, Rahmig K, Stieber P et al. Methylation of NEUROG1 in serum is a sensitive marker for the detection of early colorectal cancer. Am. J. Gastroenterol. 106(6), 1110–1118 (2011).
  Medline CASGoogle Scholar
• 121 Lofton-Day C, Model F, Devos T et al. DNA methylation biomarkers for blood-based colorectal cancer screening. Clin. Chem. 54(2), 414–423 (2008).
  Medline CASGoogle Scholar
• 122 Grutzmann R, Molnar B, Pilarsky C et al. Sensitive detection of colorectal cancer in peripheral blood by septin 9 DNA methylation assay. PLoS ONE 3(11), e3759 (2008).
  MedlineGoogle Scholar
• 123 Tanzer M, Balluff B, Distler J et al. Performance of epigenetic markers SEPT9 and ALX4 in plasma for detection of colorectal precancerous lesions. PLoS ONE 5(2), e9061 (2010).
  MedlineGoogle Scholar
• 124 Li M, Chen W-D, Papadopoulos N et al. Sensitive digital quantification of DNA methylation in clinical samples. Nat. Biotechnol. 27(9), 858–863 (2009).
  MedlineGoogle Scholar
• 125 Amiot A, Mansour H, Baumgaertner I et al. The detection of the methylated Wif-1 gene is more accurate than a fecal occult blood test for colorectal cancer screening. PLoS ONE 9(7), e99233 (2014).
  MedlineGoogle Scholar
• 126 Abbaszadegan MR, Tavasoli A, Velayati A et al. Stool-based DNA testing, a new noninvasive method for colorectal cancer screening, the first report from Iran. World J. Gastroenterol. 13(10), 1528–1533 (2007).
  Medline CASGoogle Scholar
• 127 Nishioka Y, Ueki T, Hokazono K, Nagayoshi K, Tanaka M. Comparative detection of aberrantly methylated DNA in preoperative and postoperative stool from patients with colorectal cancers. Int. J. Biol. Markers 30(1), e81–e87 (2015).
  Medline CASGoogle Scholar
• 128 Ausch C, Kim YH, Tsuchiya KD et al. Comparative analysis of PCR-based biomarker assay methods for colorectal polyp detection from fecal DNA. Clin. Chem. 55(8), 1559–1563 (2009).
  Medline CASGoogle Scholar
• 129 Baek YH, Chang E, Kim YJ, Kim BK, Sohn JH, Park DI. Stool methylation-specific polymerase chain reaction assay for the detection of colorectal neoplasia in Korean patients. Dis. Colon Rectum 52(8), 1452–1459 (2009).
  MedlineGoogle Scholar
• 130 Imperiale TF, Ransohoff DF, Itzkowitz SH et al. Multitarget stool DNA testing for colorectal-cancer screening. N. Engl. J. Med. 370(14), 1287–1297 (2014).
  Medline CASGoogle Scholar
• 131 Azuara D, Rodriguez-Moranta F, De Oca J et al. Novel methylation panel for the early detection of colorectal tumors in stool DNA. Clin. Colorectal Cancer 9(3), 168–176 (2010).
  Medline CASGoogle Scholar
• 132 Nagasaka T, Tanaka N, Cullings HM et al. Analysis of fecal DNA methylation to detect gastrointestinal neoplasia. J. Natl Cancer Inst. 101(18), 1244–1258 (2009).
  Medline CASGoogle Scholar
• 133 Glöckner SC, Dhir M, Yi JM et al. Methylation of TFPI2 in stool DNA: a potential novel biomarker for the detection of colorectal cancer. Cancer Res. 69(11), 4691–4699 (2009).
  Medline CASGoogle Scholar
• 134 Itzkowitz SH, Jandorf L, Brand R et al. Improved fecal DNA test for colorectal cancer screening. Clin. Gastroenterol. Hepatol. 5(1), 111–117 (2007).
  Medline CASGoogle Scholar
• 135 Devos T, Tetzner R, Model F et al. Circulating methylated SEPT9 DNA in plasma is a biomarker for colorectal cancer. Clin. Chem. 55(7), 1337–1346 (2009).
  Medline CASGoogle Scholar
• 136 Mandel JS, Bond JH, Church TR et al. Reducing mortality from colorectal-cancer by screening for fecal occult blood. N. Engl. J. Med. 328(19), 1365–1371 (1993).
  Medline CASGoogle Scholar
• 137 Eriksson JE, Dechat T, Grin B et al. Introducing intermediate filaments: from discovery to disease. J. Clin. Invest. 119(7), 1763–1771 (2009). •• The authors demonstrated the efficacy of methyated biomarkers for colorectal cancer detection.
  Medline CASGoogle Scholar
• 138 Hovestadt V, Jones DT, Picelli S et al. Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature 510(7506), 537–541 (2014). • The authors were the first to combine whole-genome bisulfite-sequencing with epigenome, transcriptome, RNA, and chromatin immunoprecipitation sequencing data to identify underlying effects of aberrant methylation in cancer genomes.
  Medline CASGoogle Scholar
• 139 Van Veldhoven K, Polidoro S, Baglietto L et al. Epigenome-wide association study reveals decreased average methylation levels years before breast cancer diagnosis. Clin. Epigenetics 7(1), 67 (2015). • The authors were among the first to apply whole-genome bisulfite sequencing in peripheral blood obtained before onset of the disease to predict increased risk of breast cancer.
  MedlineGoogle Scholar
• 140 Dedeurwaerder S, Defrance M, Calonne E, Denis H, Sotiriou C, Fuks F. Evaluation of the Infinium Methylation 450K technology. Epigenomics 3(6), 771–784 (2011).
  CASGoogle Scholar
• 141 Sandoval J, Heyn H, Morán S et al. Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome. Epigenetics 6(6), 692–702 (2011).
  Medline CASGoogle Scholar
• 142 Adorjan P, Distler J, Lipscher E et al. Tumour class prediction and discovery by microarray-based DNA methylation analysis. Nucleic Acids. Res. 30(5), e21 (2002).
  MedlineGoogle Scholar
• 143 Fernandez AF, Assenov Y, Martin-Subero JI et al. A DNA methylation fingerprint of 1628 human samples. Genome Res. 22(2), 407–419 (2012). • The authors were the first to apply DNA methyaltion microarray to identify a fingerprint of CpCs that determined the origin of unknown primary origin.
  Medline CASGoogle Scholar
• 144 Chuang JC, Warner SL, Vollmer D et al. S110, a 5-Aza-2′-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. Mol. Cancer Ther. 9(5), 1443–1450 (2010).
  Medline CASGoogle Scholar
• 145 Yoo CB, Jeong S, Egger G et al. Delivery of 5-Aza-2′-deoxycytidine to cells using oligodeoxynucleotides. Cancer Res. 67(13), 6400–6408 (2007).
  Medline CASGoogle Scholar
• 146 Piekarz RL, Bates SE. Epigenetic modifiers: basic understanding and clinical development. Clin. Cancer Res. 15(12), 3918–3926 (2009).
  Medline CASGoogle Scholar
• 147 Ji BT, Chow WH, Hsing AW et al. Green tea consumption and the risk of pancreatic and colorectal cancers. Int. J. Cancer 70(3), 255–258 (1997).
  Medline CASGoogle Scholar
• 148 Fang MZ, Wang Y, Ai N et al. Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res. 63(22), 7563–7570 (2003).
  Medline CASGoogle Scholar
• 149 Lee WJ. Mechanisms for the inhibition of DNA methyltransferases by tea catechins and bioflavonoids. Mol. Pharmacol. 68(4), 1018–1030 (2005).
  Medline CASGoogle Scholar
• 150 Yuasa Y, Nagasaki H, Akiyama Y et al. DNA methylation status is inversely correlated with green tea intake and physical activity in gastric cancer patients. Int. J. Cancer 124(11), 2677–2682 (2009).
  Medline CASGoogle Scholar
• 151 Fang M, Chen D, Yang CS. Dietary polyphenols may affect DNA methylation. J. Nutr. 137(Suppl. 1), S223–S228 (2007).
  Medline CASGoogle Scholar
• 152 Reuter S, Gupta SC, Park B, Goel A, Aggarwal BB. Epigenetic changes induced by curcumin and other natural compounds. Genes Nutr. 6(2), 93–108 (2011).
  Medline CASGoogle Scholar
• 153 Liu HL, Chen Y, Cui GH, Zhou JF. Curcumin, a potent anti-tumor reagent, is a novel histone deacetylase inhibitor regulating B-NHL cell line Raji proliferation. Acta. Pharmacol. Sin. 26(5), 603–609 (2005).
  Medline CASGoogle Scholar
• 154 Link A, Balaguer F, Shen Y et al. Curcumin modulates DNA methylation in colorectal cancer cells. PLoS ONE 8(2), e57709 (2013).
  Medline CASGoogle Scholar
• 155 Meeran SM, Patel SN, Tollefsbol TO. Sulforaphane causes epigenetic repression of hTERT expression in human breast cancer cell lines. PLoS ONE 5(7), e11457 (2010).
  MedlineGoogle Scholar
• 156 Hsu A, Wong CP, Yu Z, Williams DE, Dashwood RH, Ho E. Promoter de-methylation of cyclin D2 by sulforaphane in prostate cancer cells. Clin. Epigenetics 3, 3 (2011).
  Medline CASGoogle Scholar
• 157 Rajendran P, Kidane AI, Yu TW et al. HDAC turnover, CtIP acetylation and dysregulated DNA damage signaling in colon cancer cells treated with sulforaphane and related dietary isothiocyanates. Epigenetics 8(6), 612–623 (2013).
  Medline CASGoogle Scholar
• 158 Yin R, Mao SQ, Zhao B et al. Ascorbic acid enhances Tet-mediated 5-methylcytosine oxidation and promotes DNA demethylation in mammals. J. Am. Chem. Soc. 135(28), 10396–10403 (2013).
  Medline CASGoogle Scholar
• 159 Wu H, Zhang Y. Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes Dev. 25(23), 2436–2452 (2011).
  Medline CASGoogle Scholar
• 160 Tahiliani M, Koh KP, Shen Y et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324(5929), 930–935 (2009).
  Medline CASGoogle Scholar
• 161 Song C-X, Szulwach KE, Fu Y et al. Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine. Nat. Biotechnol. 29(1), 68–72 (2011).
  Medline CASGoogle Scholar
• 162 Ito S, Shen L, Dai Q et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333(6047), 1300–1303 (2011). • The authors discovered previously unknown products of TET proteins in genomic DNA. This study suggests that TET-catalyzed oxidation is followed by decarboxylation during DNA demethylation.
  Medline CASGoogle Scholar
• 163 Chen J, Guo L, Zhang L et al. Vitamin C modulates TET1 function during somatic cell reprogramming. Nat. Genet. 45(12), 1504–1509 (2013).
  Medline CASGoogle Scholar
• 164 Ichimura N, Shinjo K, An B et al. Aberrant TET1 methylation closely associated with CpG island methylator phenotype in colorectal cancer. Cancer Prev. Res. 8(8), 702–711 (2015).
  Medline CASGoogle Scholar